NM_004883.3:c.2121C>G

Variant names:

• chr5-139848349-G-C
• rs1195004358
• NM_004883.3:c.2121C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004883.3(NRG2):​c.2121C>G​(p.Ile707Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,220,662 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000061 (1 hom.)
• Consequence: NRG2 NM_004883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35
• Publications: 1 publications found

Genes affected

NRG2 (HGNC:7998): (neuregulin 2) This gene encodes a novel member of the neuregulin family of growth and differentiation factors. Through interaction with the ERBB family of receptors, this protein induces the growth and differentiation of epithelial, neuronal, glial, and other types of cells. The gene consists of 12 exons and the genomic structure is similar to that of neuregulin 1, another member of the neuregulin family of ligands. The products of these genes mediate distinct biological processes by acting at different sites in tissues and eliciting different biological responses in cells. This gene is located close to the region for demyelinating Charcot-Marie-Tooth disease locus, but is not responsible for this disease. Alternative transcript variants encoding distinct isoforms have been described. [provided by RefSeq, May 2010]

NRG2 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000250692 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004883.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG2	NM_004883.3	MANE Select	c.2121C>G	p.Ile707Met	missense	Exon 10 of 10	NP_004874.1	O14511-1
	NRG2	NM_013982.3		c.2145C>G	p.Ile715Met	missense	Exon 11 of 11	NP_053585.1	O14511-3
	NRG2	NM_013983.3		c.2127C>G	p.Ile709Met	missense	Exon 11 of 11	NP_053586.1	O14511-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRG2	ENST00000361474.6	TSL:1 MANE Select	c.2121C>G	p.Ile707Met	missense	Exon 10 of 10	ENSP00000354910.1	O14511-1
	NRG2	ENST00000358522.7	TSL:1	c.2127C>G	p.Ile709Met	missense	Exon 11 of 11	ENSP00000351323.3	O14511-4
	NRG2	ENST00000289422.11	TSL:5	c.2145C>G	p.Ile715Met	missense	Exon 11 of 11	ENSP00000289422.7	O14511-3

Frequencies

GnomAD3 genomes AF: 0.0000672 AC: 10 AN: 148726 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000201

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000894

Gnomad OTH AF: 0.000484

GnomAD4 exome AF: 0.0000606 AC: 65 AN: 1071936 Hom.: 1 Cov.: 34 AF XY: 0.0000749 AC XY: 38 AN XY: 507126

African (AFR) AF: 0.00 AC: 0 AN: 21988

American (AMR) AF: 0.000396 AC: 3 AN: 7578

Ashkenazi Jewish (ASJ) AF: 0.0000747 AC: 1 AN: 13386

East Asian (EAS) AF: 0.00 AC: 0 AN: 24344

South Asian (SAS) AF: 0.00 AC: 0 AN: 21466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21338

Middle Eastern (MID) AF: 0.000706 AC: 2 AN: 2834

European-Non Finnish (NFE) AF: 0.0000546 AC: 50 AN: 916366

Other (OTH) AF: 0.000211 AC: 9 AN: 42636

GnomAD4 genome AF: 0.0000672 AC: 10 AN: 148726 Hom.: 0 Cov.: 29 AF XY: 0.0000551 AC XY: 4 AN XY: 72580

African (AFR) AF: 0.00 AC: 0 AN: 40950

American (AMR) AF: 0.000201 AC: 3 AN: 14934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000894 AC: 6 AN: 67138

Other (OTH) AF: 0.000484 AC: 1 AN: 2064

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000106

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.0068	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.97	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.36
MutPred		0.59		Loss of stability (P = 0.189)
MVP		0.57
MPC		1.9
ClinPred		0.91	D
GERP RS		2.7
Varity_R		0.57
gMVP		0.23
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1195004358; hg19: chr5-139227934;